High Frequency of Pathogenic Germline Variants Observed in Patients With Osteosarcoma

Germline genetic testing may be warranted for patients with osteosarcoma, according to findings from a study by Lisa Mirabello, PhD, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, and colleagues (JAMA Oncol. 2020 Mar 19. Epub ahead of print).

“Osteosarcoma…occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear,” explained Dr Mirabello et al, who sought to evaluate the germline genetic architecture of patients with the disease.

Between April 21, 2014, and September 1, 2017, the investigators conducted whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients (mean age at diagnosis, 16 years) with osteosarcoma from 10 participating centers or studies.

These findings were then compared with the DNA of 1062 cancer-free individuals from 4 participating studies who underwent comparable whole-exome sequencing and 27,173 individuals of identified via the Exome Aggregation Consortium (ExAC) database.

“In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons,” Dr Mirabello and co-investigators said.

Patients were compared with individuals in the ExAC group, with the main end points being the frequency of rare pathogenic or likely pathogenic genetic variants.

Data analysis took place between June 1, 2017, and July 1, 2019.

Ultimately, a significantly higher pathogenic or likely pathogenic variant burden was observed in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma versus without cancer (732 vs 994, respectively; P = 1.3 × 10-18).

The researchers also observed pathogenic or likely pathogenic cancer-susceptibility gene variant in 281 (28.0%) of 1004 patients with osteosarcoma, approximately 75% of whom had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene.

A pathogenic or likely pathogenic cancer-susceptibility gene variant occurred regularly in 128 (12.1%) of 1062 individuals in the control group and 2527 (9.3%) of 27,173 individuals in the ExAC group.

“A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg, CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX) and in…TP53,” Dr Mirabello and colleagues said.

“In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing,” they concluded.—Hina Porcelli